As is well known, atherosclerosis is a very important factor causative of various cardiovascular disorders, and extensive and intensive studies have been conducted with a view to suppression of the progress of atherosclerosis or regression of atherosclerosis. In particular, the efficacy of a drug for lowering cholesterol in the serum or arterial wall is recognized. However, an ideal drug having a significant clinical effect and less liable to occurrence of an adverse effect has not been realized in the art.
In recent years, it has become apparent that the accumulation of a cholesterol ester in the arterial wall is an important factor causative of the progress of atherosclerosis. Therefore, lowering the cholesterol level in the blood is useful for suppression of the progress of atherosclerosis and regression of atherosclerosis.
Cholesterol in foods is esterified in tunica mucosa intestini tenuis and then incorporated as chylomicron in the blood. It is known that Acyl-CoA: Cholesterol Acyltransferase (ACAT) plays an important role in the formation of a cholesterol ester in the tunica mucosa intestini tenuis or arterial wall. Therefore, it is considered that the inhibition of ACAT in the tunica mucosa intestini tenuis to prevent the esterification prevents the absorption of the cholesterol, which contributes to lowering the cholesterol level in the blood.
In the arterial wall, the cholesterol is accumulated as a cholesterol ester. Therefore, it is expected that the inhibition of ACAT in the arterial wall can effectively prevent the accumulation of the cholesterol ester.
Thus, an ACAT inhibitor is considered likely to become a drug useful for treating hyperlipidemia and atherosclerosis through the prevention of the cholesterol absorption in intestinum tenue and the accumulation of the cholesterol in the arterial wall.
For example, urea derivatives (see, for example, J. Med. Chem., vol. 29, 1131 (1986) and Japanese Unexamined Patent Publication (Kokai) Nos. 63-316761 and 1-93569) and amide derivatives (see, for example, Japanese Examined Patent Publication (Kokoku) No. 63-54718 and Japanese Unexamined Patent Publication (Kokai) No. 63-253060) have hitherto been reported as such an ACAT enzyme inhibitor. These compounds are different from the compounds of the present invention in their structures.
On the other hand, U.S. Pat. No. 4,415,741 describes a benzopyran derivative. However, no specific disclosure of the compounds of the present invention is found therein, and up to now, it has been unknown that benzopyran derivatives have an ACAT inhibitory activity. 6-Acylaminochromanones with anti-hyperlipidemic activity (see, for example, Japanese Examined Patent Publication (Kokoku) Nos. 60-15626 and 60-35346) are known in the art. These compounds, however, are inferior to the compounds of the present invention in the activity thereof, and it was unknown that they have an ACAT inhibitory activity. Further, chromanones having a urea group on their aromatic ring (see J. Med. Chem., vol. 13, 584 (1970)) and 8-acylaminobenzopyrans having a leukotriene antagonism (see, for example, Japanese Unexamined Patent Publication (Kokai) Nos. 61-50977, 61-126061, 61-143371 and 62-230760 and J. Med. Chem., vol. 31, 84 (1988)) and 8-acylaminochromanones having a local anesthetic action (see Khim. Getrotsikl. Soedin., 320 (1987)) are also known in the art. However, it was unknown that they have an anti-hyperlipidemia activity and an ACAT inhibitory activity.